Mono- and disulfo-substituted anthraquinones and their use for the treatment of bone matrix disorders

ABSTRACT

Compounds of formula (I) for treatment of pathologies in which erosion of cartilaginous and bone matrix occurs, for example osteoarthrosis. An exampliary compound is 2,6-anthraquinonesulfonamido-N,N-caproic acid. ##STR1##

This is the U.S. National Stage Application of PCT/EP96/02597 filed Jun.17, 1996 now WO/97/00875 published Jan. 9, 1997.

The present invention relates to compounds useful for the treatment ofthe pathologies in which the erosion of the cartilaginous and bonematrix occurs in the most advanced steps of the disease, such asosteoarthrosis and rheumatoid arthritis, and to pharmaceuticalcompositions containing them. Furthermore, the invention relates tonovel anthraquinone derivatives and to the process for the preparationthereof.

Osteoarthrosis are known to be treated mainly using substances acting onthe pain and exerting their symptomatic effect thanks to theirantiinflammatory activity. Said medicaments are usually referred to asnon steroidal antiinflammatory drugs (NSAID) such as for exampleindomethacin and steroidal ones, such as hydrocortisone andbethametasone.

Other used compounds comprise copper chelating agents, such aspenicillamine, and those compounds which interfere with collagenesynthesis, with DNA or with synovial membranes, such ascyclophosphamide.

Among the most recent substances used in the above mentioned pathologiesthere are diacetylrhein, a pro-drug of rhein, which exerts itstherapeutical activity being a copper chelating agent, moreover itinhibits the formation of ceruloplasmin during the acute phase ofarthritis inflammation and it is also a calcium chelating agent, formingsoluble complexes with calcium thanks to the solubilizing COOH grouppresent in its structure. Such a characteristic of forming solublecomplexes with calcium is likely to be of paramount importance, since itavoids the formation and precipitation of microcrystals at thearticulation sites, thereby preventing inflammatory reactions fromoccurring or from going on (Friedman, U.S. Pat. No. 4,244,968 del 13,Jan. 1981). Furthermore, rhein inhibits the formation and release of thesuperoxide anion from NADPH-dependent biological systems (Mian M. et al.J. Pharm. Pharmacol. 1987; 39: 845-847) and the activity of serineproteases, such as elastase and cathepsin G from man (Raimondi I. et al.Pharmacol. Res. Comm. 1982; 14 (2): 103-112), Zembower D E. et al. J.Med. Chem. 1992; 35: 1597-1605 1992).

Further pharmacological and clinical studies described in literatureproved that, in addition to the above mentioned mechanisms, otherpathogenetic mechanisms act in the diseases affecting articulations,causing the erosion of the cartilaginous and bone matrix.

Among such mechanisms, the increase in some enzyme activities or anunbalance among the latter and the inhibitors thereof should bestressed. As recently proved by some researchers, cysteine proteases,such as cathepsin B and L, are enzymes strictly connected with thedegradation of the cartilage and therefore with the related pathologies.It has widely been reported in literature, that cysteine proteases,cathepsins B and L, are capable of inducing directly or indirectly (byactivation of proenzymes), the degradation of the main components of thecartilaginous and bone extracellular matrix (Roughley P J. et al.Biochem. J. 1977; 167; 639-637; Sakamoto S. et al. MOL. Aspects Med.1988; 10; 299-428; Nguyen P j. et al. Biochem. J. 1991 Aug. 15; 278 (pt1): 143-7; Maciewiez R A. et al. Biomed. Biochim. Acta 1991; 50 (4-6):561-4; Buttle D J. Arthritis Rheum. 1993; 36 (12); 1709-17; Pelletier JP. et al. Osteoarthritis 1993; 19 (3); 545-568).

Moreover, the interest in these enzyme activities, has been confirmed bystudies carried out on laboratory animals (rats) in which rheumatoidarthritis had been induced. In said animals, the effect of theinhibitors of cysteine proteases, such as fluoromethylketones, on thedevelopment of the disease was evaluated particularly on thecartilaginous and bone articular lesions.

The results of said studies showed that the enzyme inhibitors can beclinically valuable in the treatment of arthritis (Ahmed N K. et al.Biochem. Pharmacol. 1992; 44 (6); 1201-7; Meijers M, Billingham M. etal. Agents actions 1993; 39 (1); 219-21; Esser R E. et al. J. Reumatol.1993; 20 (7); 1176-83).

Other authors (Gabrijelcic D. et al. J. Clin. Chim. Biochem. 1990; 28(3); 149-53) evidenced the presence of cathepsin B and H in the synovialfluid of patients with different diseases of the articulation whereasMartel-Pelletier J. et al., J. Orthop. (1990): 8 (3:336) proved theexistence of an unbalance between the levels of cathepsin B and theinhibitors thereof in the cartilaginous tissue of osteoarthrosicpatients.

Huet et al. Arthritis Rheum. (1993): 36 (3): 772 showed that IL-1 andTNF stimulate the activity of cysteine proteases in synovial cells ofexplants from patients affected with osteoarthrosis and arthritis.

From what stated above, it is clear that cysteine proteases are activelyinvolved in the osteoarthrosic and arthritic pathologies, therefore theuse of a therapeutical agent markedly inhibiting the activity of saidproteases is widely justified.

Now it has surprisingly been found that anthraquinone mono- anddisulfonic acid derivatives have remarkable activity against cysteineproteases.

It is an object of the present invention the use for the preparation ofa medicament useful for the treatment of pathologies in which theerosion of the cartilaginous and bone matrix occurs in the most advancedsteps of the disease, in particular osteoarthrosis and rheumatoidarthritis, of the compounds of general formula (I) ##STR2## wherein: Ais a group of formula --SO₃ R, in which R is hydrogen or a cationcapable of giving a water-soluble derivative;

or

A is a group of formula --SO₂ R¹, wherein R¹ is a --NR² R³ group, inwhich R² is hydrogen or C₁ -C₆ straight or branched alkyl,

R³ is --CH(COOH)--R⁵, wherein R⁵ is C₁ -C₆ alkyl or C₇ -C₁₂ arylalkyl;--(CH₂)_(n) --COOH, wherein n is a integer from 1 to 6, C₁ -C₆ straightor branched alkyl, --C₆ H₄ --O--(CH₂)_(m) --CH₃, wherein m is a integerfrom 1 to 4;

or

R¹ is a --OR⁴ group, in which R⁴ is a C₁ -C₆ straight or branched alkylgroup or an optionally substituted C₆ -C₁₀ aryl group;

B is a hydrogen atom;

or

B has the same meanings as A; with the proviso that A and B aresimultaneously --SO₃ R or --SO₂ R¹.

With the expression "a cation capable of giving a water-solublederivative", those skilled in the art can evaluate which cations areable to play the solubilizing function and, at the same time, to giverise to non-toxic derivatives which do not affect adversely thepharmacological activity of the compounds of formula (I). Examples ofsaid type of cation are metal cations such as lithium, sodium,potassium.

Examples of C₁ -C₆ straight or branched alkyl group are methyl, ethyl,propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl.

Examples of C₇ -C₁₂ arylalkyl group are benzyl, 2-phenylethyl,1-phenylethyl, 3-phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl.

Examples of C₆ -C₁₀ group are phenyl, naphthyl. Optional substituentsgroups can be for example amino, mono- or of-(C₁ -C₆)-alkylamino, suchas diethylamino, hydroxy, C₁ -C₆ alkoxy, such as isopropoxy, thio.

The following novel compounds according to the present invention areincluded within the above general formula:

2,6-anthraquinonesulfonamido-N,N-caproic acid;

N,N'-diethyl-2,6-anthraquinonedisulfonamide;

N,N'-(p-ethoxyphenyl)-2,6-anthraquinonedisulfonamide;

bis-2-(2,6-anthraquinonedisulfon)-N,N'-diamidopropionic acid;

bis-2-(2,6-anthraquinonedisulfon)-N,N-diamido-3-phenyl-propionic acid.

Anthraquinone dibasic sulfonamides with antiviral activity have beendescribed by M. Grisar et al. in Journal of Medicinal Chemistry, 1974,vol. 17, n. 8, p. 890-893.

Anthraquinone sulfonamides are described in GB 2025954 to be generallyuseful as intermediates for dyes, chemical products for agriculture andpharmaceuticals. Particularly, they are described as components ofaqueous solutions for removing hydrogen sulfide from gases.

The compounds of the invention can be prepared from anthraquinone mono-and/or disulfonic acid by means of the intermediates: ##STR3## in whichX is a halogen, in particular chlorine.

Such an intermediate is known to be prepared reacting mono or disulfonicacid with chlorosulfonic acid or with phosphorous pentachloride or withphosphorous oxychloride or with mixtures of the last two.

The resulting halogenated derivative is reacted with a compound ofgeneral formula HNR² R³.

The technique which can be applied to the latter step varies with thetype of R² and R³, the purity and the obtainable yields. In some cases,the sulfonic acid chloride is reacted with a HNR² R³ strong excess,whereas in other cases it is preferred to carry out the reaction in asuitable solvent; as examples of appropriate solvents, ethyl ether andmethylene chloride can be mentioned. When the presence of a base issuitable, preferred are those such as amines, for example triethylamineand paradimethylaminopyridine.

The reaction conditions depend on the nature of the reagents, thesolvent and the presence or the absence of a base as well as its amount,if any. Temperatures range from -10° C. and the solvent boiling point.The most suited operative conditions range from 5° C. to 30° C. Thereaction times vary depending on other parameters, but they usuallyrange from 2 hours to 3 days.

Analogously, the halogenated derivative is reacted with a R¹ OH alcohol,wherein R¹ is C₁ -C₆ alkyl, thereby obtaining the sulfonic acid ester.The preferred method consists in reacting the sulfonic acid sodium saltwith chlorosulfonic acid in excess at room temperature for about 24hours.

After that, sulfonyl chloride is recovered by filtration, afterhydrolysis of the chlorosulfonic acid excess with water and ice.Sulfonyl chloride is reacted with an amine HNR¹ R² or with an alcohol R³OH, in which R¹, R², R³ have the meanings defined above, preferably atroom temperature and in the presence of tertiary amines, particularly inwhen operating in a solvent.

Anthraquinone mono- and disulfonic acids and substituted derivatives ofthe present invention are remarkably effective in variouspharmacological tests.

By way of example, the experimental results of some enzyme tests carriedout with mono- and disulfonic derivatives having SO₃ R groups at thepositions 1,5 and 2,6 are reported (see Tables 1 and 2).

Effects on human cathepsin B and L enzymatic activity

The anthraquinone monosulfonated and disulfonated compounds weredissolved in distilled water whereas the derivatives thereof weredissolved in dimethylsulfoxide. The concentration of the tested productwas added to the reaction mixture in a volume of 100 μl.

Composition of the reaction mixture: 0.005M acetate buffer pH 6.0+2 mMcysteine+1 mM EDTA; Enzyme 1 U/ml (cathepsin B or L) (Calbiochem);substrate 0.2 mM Z-Phe-Arg-AMC (Novabiochem) final reaction volume 2 ml;temperature 25° C.; observation time for cathepsin B: 2 minutes; for L:8 minutes. This is a fluorimetric determination wherein the excitationwavelength was 380 nm, the emission one being instead 460 nm.Fluorescence was read by means of a Perkin-Elmer spectrophotometer mod.LS-3B.

Studied concentrations

Anthraquinone-2,6-disulfonic acid: 1-5-10 μM

Anthraquinone-1,5-disulfonic acid: 1-5-10 μM

N,N'-(p-Ethoxyphenyl)-2,6-anthraquinone-disulfonamide: 1-10 μM.

The results reported in Tables 1 and 2 show that the tested compoundsmarkedly inhibit the activity of cathepsins B and L from humans.

                  TABLE 1    ______________________________________    EFFECT OF ANTHRAQUINONE MONO- AND DISULFONIC    ACIDS ON HUMAN CATHEPSIN B ENZYMATIC ACTIVITY            Conc. Experiment n.  % Inhibition    Compound  μm   1      2      3    M    ______________________________________    2,6-anthra-              10      98.9   98.2   87.7 94.9    quinonedisul-              5       68.5   65.8   76.0 70.1    fonic acid              1       43.7   33.7   38.5 40.7    Acid 1,5-an-              10      55.1   36.6   41.6 44.4    thraquinonedi-              5       10.3   7.2    11.4 9.6    sulfonic acid              1       4.1    3.6    2.5  3.4    N,N'-(p-ethoxy-              10      76.6   80.6   83.4 80.2    phenyl)-2,6-              1       23.7   18.6   14.8 19.0    anthraquinone-    disulfonamide    ______________________________________

                  TABLE 2    ______________________________________    EFFECT OF ANTHRAQUINONE MONO- AND DISULFONIC    ACIDS ON HUMAN CATHEPSIN L ENZYMATIC ACTIVITY            Conc. Test n.        % Inhibition    Compound  μm   1      2      3    M    ______________________________________    2,6-anthra-              10      92.1   96.5   94.8 94.5    quinonedi-              1       39.6   31.4   35.8 35.6    sulfonic acid    1,5-anthra-              10      48.6   60.5   53.9 54.3    quinonedi-              1       10.5   8.4    5.5  8.1    sulfonic acid    N,N'-(p-ethoxy-              10      53.6   48.1   63.8 55.2    phenyl)-2,6-              1       8.5    7.1    10.9 8.8    anthraquinone-    disulfonamide    ______________________________________

Adjuvant arthritis

The test evaluates the effect of the compoundsanthraquinone-2,6-disulfonic acid andN,N'-diethylanthraquinone-2,6-disulfonamide on rheumatoid arthritis inthe rat induced by administration of complete Freund's adjuvant.Diacetylrhein was used as control.

For the test, albino Sprague Dawley rats weighing 200±10 g, weresubdivided into four groups of six animals each. All of the compoundswere administered orally at a dosage of 20 mg/kg. Arthritis was inducedadministering all the animals, in the left rear paw, with 5 mg ofFreund's complete adjuvant suspended in 0.05 ml of paraffin oil (priorto the treatment, the paw volume of both rear paws was measured). Thetreatment with the tested products started 5 days after the arthritisinduction and was carried out for ten days. Al the end of this time, theanimals were killed to effect the analysis of the following evaluationparameters: measurement of the volume of both left and right rear paws;Rx in lateral and antero-posterior position of the tibio-tarsalarticulation of the left paw; histology evaluation of the articulationof both left and right rear paws.

The obtained results show that the compoundsanthraquinone-2,6-disulfonic acid andN,N'-diethylanthraquinone-2,6-disulfonamide inhibit by 18.6 and 21.4%respectively the increase in the volume of the left rear paw, whereasdiacetylrhein caused an 8.3% reduction. The effect of the twodisulfonated compounds on the increase in the volume of the right pawwas much more marked. In fact, an inhibition of respectively 67.5 and62.3% (acid anthraquinone-2,6-disulfonic acid andN,N'-diethylanthraquinone-2,6-disulfonamide) was observed, versus acomplete lack in activity by diacetylrhein (see Table 3). Furthermore,radiographies show that the two disulfonated compounds inhibit theirloss in bone mass and significantly protect the tibio-tarsalarticulation It is indeed evident from the histological examination ofthe latter, that the disulfonated compounds markedly inhibit theformation of fibrous tissue in the articulation whereas this isremarkably present in the articulation of the control groups and inthose treated with diacetylrhein.

                  TABLE 3    ______________________________________    EFFECT OF ANTHRAQUINONE MONO- AND    DISULFONIC ACIDS IN THE OEDEMA    INDUCED BY FREUND'S COMPLETE ADJUVANT                        Volume increase in the oedema             Dose       after 15 days    Compound   mg/kg/os     Left paw Right paw    ______________________________________    Control    --           252 ± 26                                     77 ± 29    Acid 2,6-an-               20           205 ± 41                                     25 ± 20    thraquinonedi-    sulfonic acid    N,N'-diethyl-               20           198 ± 31                                     29 ± 12    2,6-anthra-    quinonedi-    sulfonamide    Diacetylrhein               20           231 ± 22                                     92 ± 30    ______________________________________

Such a protecting activity is also evidenced by the histologicalexaminations carried out on the rat tibio-tarsal articulation.

Contrary to rhein, said products are nor copper neither calciumchelating agents, they do not inhibit the production and the release ofthe superoxide anion from NADPH-dependent biological systems, do notinhibit the activity of superoxide dismutase, they are not serineproteases inhibitors, they are not mutagenic in the Ames test and causeno chromosomal aberrations as well.

Test of induction of chromosomal aberrations

The clastogenetic effect of rhein and of 2,6-anthraquinonedisulfonicacid, was evaluated using the test of the induction of chromosomalaberrations in cell cultures of chinese hamster ovary (CHO). In thistest, the cell line was treated with the tested substances and withsuitable controls, in the presence of a metabolic activation system forfour hours. After that, the cell in growth exponential phase weretreated with colchicine (Colcemid^(R)) for 90 minutes, so as to obtain asignificant number of cells in metaphase and to recover them for thepreparation of the chromosome suspension. As the positive standard,cyclophosphamide was used (1-5-10-12.5-25 μg/ml).

The toxicity of the tested compounds was evaluated by means of the assayof the efficiency of plating, treating the cells for four hours, thenseeding them at a concentration of 200 cells/5 ml of fresh culturemedium.

On the ground of the results obtained by means of this test, dosageswere selected for the treatment in the test of induction of chromosomalaberrations, so as not to exceed, with the highest dosage, 50% toxicitylevels.

The selected doses were:

rhein: 25-50-100-200 μg/ml

Acid 2,6-anthraquinonedisulfonic acid: 50-100-150-200-250 μg/ml.

The chromosomal aberrations were recorded describing the type ofstructural damage. The numeric aberrations and gaps were discarded.Metaphases showing a good chromosomal opening, a good staining and anacceptable chromosome number (20±2) were selected. For statisticalevaluations of the results, the quadratic Chi test was used.

The results prove that the compound 2,6-anthraquinonedisulfonic acidinduces no chromosomal aberrations whereas rhein is positive at doses of100 and 200 μg/ml (see Tables 4 and 5).

                  TABLE 4    ______________________________________    CHROMOSOMAL ABERRATION ASSAY    ON CHINESE HAMSTER OVARY CELLS                      Total meta-                                Metaphases with    Compound Dose     phases    aberrations                                          P    ______________________________________    Control +             //       220       13    S - 9    CPS +     10 μg/ml                      32        12        P < 0.001    S - 9     5 μg/ml                      100       25        P < 0.001              1 μg/ml                      100       10        N.S.    2,6-an-  250 μg/ml                      100       6         N.S.    thraqui- 200 μg/ml                      100       8         N.S.    none     150 μg/ml                      100       8         N.S.    sulfonic 100 μg/ml                      100       4         N.S.    acid +    50 μg/ml                      100       2         N.S.    S - 9    ______________________________________     CPS = Cyclophosphamide     S  9 = metabolic activation system

                  TABLE 5    ______________________________________    CHROMOSOMAL ABERRATION ASSAY    ON CHINESE HAMSTER OVARY CELLS                    Aber-            Aber-            Dose    rations  Aberrations                                     rations    Compound            (μg/ml)                    simple (S)                             complex (C)                                     S + C  P    ______________________________________    Control //      8        4       12    400 me-    taphases    CPS     25      0        87      87     P < 0.001    100 me- 12.5    0        44      44     P < 0.001    taphases    Rhein   200     3        5       8      P < 0.05    100 me- 100     3        6       9      P < 0.05    taphases            50      1        3       4      N.S.            25      1        1       2      N.S.    ______________________________________

Therefore, such characteristics markedly differentiate the compounds ofthe invention from rhein.

Action of disulfonated anthraquinone on copper "scavenging" effect

The study involves the production of superoxide anion by means of thehypoxanthine/xanthine oxidase system and the target is the reduction incytochrome C iron content. Copper is known to be capable of capturingthe radical produced by said system. Copper chelants inhibit such a"scavenging" effect.

Table 6 shows that rhein inhibits said effect, whereas the compounds1-anthraquinonesulfonic acid and 2-anthraquinonesulfonic acid are nearlyinactive.

                  TABLE 6    ______________________________________    EFFECT ON COPPER "SCAVENGING" ACTION    Compound      % Reduction    ______________________________________    1-AQ          3    2-AQ          5    1,5-AQ        4    2,6-AQ        6    rhein         45    ______________________________________     1-AQ: anthraquinone1-sulfonic     2AQ: anthraquinone2-sulfonic     1,5AQ: anthraquinone1,5-disulfonic acid     2,6AQ: anthraquinone2,6-disulfonic acid

The present invention also relates to pharmaceutical compositionscontaining a therapeutically effective amount of a compound of formula Iin admixture with conventional carriers and excipients.

The compositions according to the invention are prepared according toknown methods, for example as described in "Remington's PharmaceuticalSciences Handbook", XVII Ed., Mack Pub. Inc., N.Y., U.S.A..

Examples of compositions for the enteral, parenteral, topicadministrations are tablets, capsules, granules, controlled-releaseformulations, liquid drinkable formulations, injectables, suppositories,creams, transdermal formulations.

In the oral formulations, the dosage of the active ingredient will rangefrom 10 to 500 mg depending on the activity of the product and on thetherapeutical uses. The systemic use will range from 1 to 100 mg.

In the following, illustrative examples are reported.

EXAMPLE 1

N,N'-Diethyl-2,6-anthraquinonedisulfonamide

13.0 g of anthraquinone-2,6-disulfonylchloride are suspended in 300 mlof methylene chloride, under strong stirring. 300 ml of diethylamine areadded thereto, by means of a dropping funnel at such a rate as not toexceed 25°-30° C., cooling, if necessary, the solution. The resultingsuspension is stirred for 6 hours, then left to stand overnight. Thesuspension is then added with 100 ml of 1N NaOH under stirring, stirredfor 2 hours and then the resulting solid is filtered, washing itthoroughly with water.

9,3 g of a product with a good purity (95-97% by HPLC) are obtained,which, if necessary, can be recrystallized from a 3/1dimethylacetamide/water solution.

IR and NMR analysis confirm the identity of the product.

EXAMPLE 2

N,N'-(p-Ethoxyphenyl)-2,6-anthraquinonedisulfonamide

15.5 ml of p-phenetidine are added to 150 ml of methylene chloride,under strong stirring. 6.1 g of anthraquinone-2,6-disulfonylchloride aregradually added, in small portions, so as not to exceed 15°-20° C.,cooling, if necessary, the solution. The resulting suspension is stirredfor 3 hours, then left to stand for 3 days; the obtained solid isfiltered, washing thoroughly with 1M hydrochloric acid and then withwater. 9.8 g of a product are obtained, which is recrystallized twicefrom dimethylacetamide/water solutions. Finally 3,8 g of the pureproduct are obtained.

IR and NMR analysis confirm the identity of the product.

EXAMPLE 3

2,6-Anthraquinonedisulfonamido-N,N'-caproic acid

16.4 g of methyl-6-aminocaproate hydrochloride, 18 ml of triethylamineand 200 mg of p-dimethyl-aminopyridine are added to 150 ml of diethylether, stirring the whole thoroughly. 6.1 g ofanthraquinone-2,6-disulfonylchloride are gradually added, in smallportions, so as not to exceed 15°-20° C., cooling, if necessary, thesolution. The resulting suspension is stirred for 3 hours at roomtemperature, then 3 hours under reflux, then it is left to standovernight; after that the solvent is evaporated off and the obtainedsolid is taken up with 35 g of KOH dissolved in 500 ml of water/methanol1/1. The mixture is stirred for 1 hour at room temperature, then isacidified with 20% hydrochloric acid to markedly acidic pH; afterstirring for 5 minutes the resulting solid is filtered, washing itthoroughly with water. 5.0 g of a product are obtained, which isrecrystallized twice from dimethylacetamide/water solutions. Finally 2.1g of the pure product are obtained.

IR and NMR analysis confirm the identity of the product.

EXAMPLE 4

    ______________________________________    Soft gelatin capsules:    Each soft gelatin capsule contains:                   1)    2)    ______________________________________    Active ingredient                     100 mg  300 mg    Soy oil           50 mg  150 mg    ______________________________________

The dispersion of the active ingredient in soy oil is dosed in softgelatin capsules using the suitable device.

The active ingredients used in this formulation are preferably:

1) --N,N'-diethyl-2,6-anthraquinonedisulfonamide

2) --N,N'-(p-ethoxyphenyl)-2,6-anthraquinonedisulfonamide.

EXAMPLE 5

    ______________________________________    Hard gelatin capsules    Each capsule contains:    ______________________________________    Active ingredient                      40 mg  200 mg    Lactose          200 mg  285 mg    Magnesium stearate                      10 mg   15 mg    ______________________________________

The products are mixed and then dosed in capsules of suitable size.

The active ingredients used in this formulation are preferably selectedfrom:

2,6- or 1,5-anthraquinonedisulfonic acid sodium salts;

2,6-anthraquinonedisulfonamido-N,N'-caproic acid.

EXAMPLE 6

    ______________________________________    Tablets    Each tablet contains:    ______________________________________    Active ingredient   250 mg  15 mg    Microcrystalline cellulose                        200 mg  800 mg    Anhydrous lactose   220 mg  97 mg    Sodium carboxymethyl starch                         21 mg   6 mg    Magnesium stearate   9 mg     2 mg.    ______________________________________

The active ingredient is mixed thoroughly with microcrystallinecellulose and the anhydrous lactose, sodium carboxymethyl starch andmagnesium stearate are added mixing again, then the resulting mixture issieved and tabletted to obtain tablets weighing 700 and 920 mgrespectively.

The active ingredients used in this formulation are preferably:

1)--N,N-diethyl-2,6-anthraquinonedisulfonamide

2)--N,N-(p-ethoxyphenyl)-2,6-anthraquinonedisulfonamide

3)--anthraquinonesulfonic acid of formula (I) sodium salts.

EXAMPLE 7

    ______________________________________    Cream    ______________________________________    Active ingredient 2.000 g    Mixture of cetyl and                      15.000 g    stearyl alcohols    Sodium lauryl sulfate                      1.500 g    Decyl oleate      10.000 g    Vaselin oil       5.000 g    Depurated water   66.000 g    Methyl-p-oxy-benzoate                      0.160 g    Propyl para-oxy-benzoate                      0.040 g    Rose essence      0.300 g    ______________________________________

The mixture of cetyl and stearyl alcohols is melted with sodiumlaurylsulfate and decyl oleate, adding the active ingredient and mixingthoroughly. The obtained product is then added to water, brought to thesame temperature at which methyl-p-oxybenzoate and propyl-p-oxybenzoatehad been dissolved, emulsified carefully in a suitable device, cooled toabout 60° C. under stirring, added with the rose essence and then cooledand distributed in suitable containers.

Particularly suitable active ingredients of the preparations are:

--N,N'-diethyl-2,6-anthraquinonedisulfonamide;

--N,N'-(p-ethoxyphenyl)-2,6-anthraquinonedisulfonamide.

EXAMPLE 8

Ointment

With similar procedures, ointments can be prepared with activeingredients consisting of the salts of the compounds of formula (I)using compositions of the following type:

    ______________________________________    Active ingredient    3.000 g    Hamamelis water      27.000 g    Cetyl alcohol        16.500 g    Free and esterified sterols                         1.000 g    Methyl p-oxybenzoate 0.150 g    Propyl gallate       0.030 g    Propylene glycol     7.000 g    Rose essence         0.250 g    Disodium versenate   0.050 g    Vitamin F 80%        1.250 g    Polyglycol esters of saturated and                         0.500 g    unsaturated fatty amides    C.sub.13 -C.sub.20    Depurated water q.s. to 100 g.    ______________________________________

EXAMPLE 9

Intramuscular vials

Each vial contains:

    ______________________________________    Active ingredient 25.00 g    Sodium chloride    3.80 g    Sodium citrate dihydrate                      25.73 g    Citric acid monohydrate                       7.87 g    Water for         q.s. to 2 ml.    injectable preparations    ______________________________________

The solution of the active ingredient and of the excipients is filteredsterilely and partitioned in vials which are subsequently sterilized inautoclave at 121° C. for 15 minutes.

The active ingredients used in this formulation are preferably theanthraquinonesulfonic acid of formula (I) sodium salts.

EXAMPLE 10

Intra-articular vials

Each vial of freeze-dried product contains

    ______________________________________    Active ingredient                     1 mg    Mannitol        50 mg    Sodium hydroxide                    q.s. to pH 6.5    ______________________________________

Each solvent vial contains

Water for injectable preparations 2 ml.

The solution of the active ingredient and of the excipients is sterilelyfiltered and partitioned in vials, then freeze-dried in a suitabledevice.

The active ingredients used in this formulation are preferably theanthraquinonesulfonic acid of formula (I) sodium salts.

I claim:
 1. A method of treatment of pathologies wherein the erosion ofthe cartilaginous and bone matrix occurs in the most advanced steps ofthe disease comprising administering a treatment effective amount of acompound of formula (I): ##STR4## wherein: A is a group of formula --SO₃R, in which R is hydrogen or a cation capable of giving a water-solublederivative;or A is a group of formula --SO₂ R¹, wherein R¹ is a --NR² R³group, in which R² is hydrogen or C₁ -C₆ straight or branched alkyl, R³is --CH(COOH)--R⁵, wherein R⁵ is C₁ -C₆ alkyl or C₇ -C₁₂ arylalkyl;--(CH₂)_(n) --COOH, wherein n is an integer from 1 to 6, C₁ -C₆ straightor branched alkyl, --C₆ H₄ --O--(CH₂)m--CH₃, wherein m is an integerfrom 1 to 4;or R' is a --OR⁴ group, in which R⁴ is a C₁ -C₆ straight orbranched alkyl group or an optionally substituted C₆ -C₁₀ aryl group; Bis a hydrogen atom;or B has the same meanings as A; with the provisothat A and B are simultaneously --SO₃ R or --SO₂ R¹.
 2. The methodaccording to claim 1, wherein the pathology is osteoarthrosis.
 3. Themethod according to claim 1, wherein the pathology is arthritis.
 4. Themethod according to claim 1, wherein the compound is selected from thegroup consisting of:2,6-anthraquinonesulfonamido-N,N-caproic acid;N,N'-diethyl-2,6-anthraquinonedisulfonamide;N,N'-(p-ethoxyphenyl)-2,6-anthraquinonedisulfonamide;bis-2-(2,6-anthraquinonedisulfon)-N,N'-diamido propionic acid;bis-2-(2,6-anthraquinonedisulfon)-N,N-diamido-3-phenyl-propionic acid.5. A compound selected from the group consistingof:2,6-anthraquinonesulfonamido-N,N-caproic acid;N,N'-diethyl-2,6-anthraquinonedisulfonamide;N,N'-(p-ethoxyphenyl)-2,6-anthraquinonedisulfonamide;bis-2-(2,6-anthraquinonedisulfon)-N,N'-diamido propionic acid;bis-2-(2,6-anthraquinonedisulfon)-N,N-diamido-3-phenylpropionic acid. 6.A process for the preparation of the compounds of claim 5, comprisingthe reaction of the corresponding anthraquinone mono- or disulfonic acidhalide with an amine.
 7. Pharmaceutical compositions containing atherapeutically effective amount of a compound of claim 1, in admixturewith pharmaceutically acceptable carriers and excipients.